HER2 Therapies in Context: Approvals, Efficacy Signals, and Future Direction

The experts review the clinical data shaping current treatment decisions for HER2-mutated NSCLC and how these data inform real-world sequencing strategies. Dr. Patel highlights results from early clinical development programs showing robust response rates for HER2-targeted TKIs, including frontline activity exceeding 70% in some studies. This underscores the transformative potential of precision therapeutics for a molecular subset historically lacking effective options.

Dr. Riess expands on the integration of HER2-directed therapies into practice, noting that multiple agents are now approved or in late-stage development. He discusses the complementary roles of zongertinib and T-DXd, describing their distinct toxicity profiles, such as interstitial lung disease/pneumonitis with ADCs and manageable GI or dermatologic toxicities with TKIs. Clinicians must proactively monitor patients, adjust doses early, and collaborate with allied health teams to ensure tolerability.

The segment also reviews the importance of molecular testing beyond initial diagnosis. HER2 amplification and overexpression are increasingly recognized as mechanisms of resistance to other targeted therapies, particularly EGFR TKIs. As such, post-progression biopsies and ctDNA testing are becoming more relevant for reassessing actionable drivers.

Finally, there is an ongoing need for clinical trial readouts to guide optimal sequencing. Although chemotherapy remains the current first-line standard in HER2-mutated disease, emerging evidence suggests that targeted therapies may eventually move earlier in the treatment course. Until definitive phase III data mature, clinicians must rely on a combination of evidence, experience, and multidisciplinary insight to determine the best approach.